Animal feed and process

ABSTRACT

An animal feed for increasing meat, milk or egg production comprising a compound of the group consisting of a 1,6disubstituted-4H-s-triazolo(4,3-a)(1,4)benzodiazepine of the formula:   WHEREIN R is a cycloalkyl of 3 to 8 carbon atoms, inclusive, wherein R1 is hydrogen, alkyl of 1 to 3 carbon atoms, inclusive, hydroxy or acetoxy wherein A is selected from the group consisting of cycloalkyl in which the ring consists of 5 to 7 carbon atoms, inclusive, and   IN WHICH R2 and R3 are selected from the group consisting of hydrogen, alkyl of 1 to 3 carbon atoms, inclusive, halogen, nitro, cyano, trifluoromethyl and alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, amino, dialkylamino, and alkanoylamino, in which the carbon moieties are of 1 to 3 carbon atoms, inclusive; Pyridyl (2, 3, or 4) and pyrimidyl; wherein R4 and R5 are defined like R2 and R3; the 5-N-oxides thereof and the pharmacologically acceptable salts and N-5 oxides thereof in combination with a nutrient animal feed.   D R A W I N G

United States Patent [191 Collins Mar. 11, 1975 ANIMAL FEED AND PROCESS [75] Inventor: Robert J. Collins, Portage, Mich.

[73] Assignee: The Upjohn Company, Kalamazoo,

Mich.

221 Filed: Aug. 6, 1973 21 Appl. No.: 385,909

Related US. Application Data [63] Continuation of Ser. No. l70,328, Aug. 9, I971,

OTHER PUBLICATIONS Archer et al-., Chem. Reviews, Vol. 68, pp. 754, 759-760, (1968).

Primary Examiner-Frederick E. Waddell Attorney, Agent, or Ftrm-1ohn J. Killinger; Roman Saliwanchik [57] ABSTRACT An animal feed for increasing meat, milk or egg production comprising a compound of the group consisting of a I,6-disubstituted-4I-I-s-triazolo[4,3- a][l,4]benzodiazepine of the formula:

R4 Formula 1 wherein R is a cycloalkyl of 3 to 8 carbon atoms, inclusive, wherein R is hydrogen, alkyl of I to 3 carbon atoms, inclusive, hydroxy or acetoxy wherein A is selected from the group consisting of cycloalkyl in which the ring consists of 5 to 7 carbon atoms, inclusive, and

in which R and R are selected from the group consisting of hydrogen, alkyl of l to 3 carbon atoms. inclusive, halogen, nitro, cyano, trifluoromethyl and alk oxy, alkylthio, alkylsulfinyl, alkylsulfonyl, amino, dialkylamino, and alkanoylamino, in which the carbon moieties are of 1 to 3 carbon atoms, inclusive; Pyridyl (2, 3, or 4) and pyrimidyl; wherein R and R are defined like R and R the 5-N-oxides thereof and the pharmacologically acceptable salts and N5 oxides thereof in combination with a nutrient animal feed.

6 Claims, No Drawings 1 ANIMAL FEED AND PROCESS CROSS REFERENCE TO RELATED APPLICATION This application is a continuation of application Ser. No. 170,328 filed Aug. 9, 1971, now abandoned.

This application is related to copending U.S. application Ser. No. 154,674, filed June 18, 1971 now abandoned, which discloses compounds of the Formula 1 and methods for their preparation.

BRIEF SUMMARY OF THE INVENTION DETAILED DESCRIPTION It has been found in recent years that meat-producing animals will gain more weight and gain it faster when various classes of compounds such as vitamins, minerals, estrogens, antibiotics, and tranquilizers are added to the diet. Although the presently available compounds are useful, new materials are still being sought that would produce weight gains more rapidly, to a greater extent, more efficiently with respect to feed intake at a lower cost and without undesirable side effects.

It is now possible by use of the present invention to obtain unexpected results in the feeding of meatproducing, milk-producing, or egg-laying animals; that is to say, an increased rate of weight gain, an increased amount of weight gain, an increase in milk production, or increased rate of egg laying, as well as increased feed efficiency, can be obtained by the addition of minute quantities of a compound of the Formula I to the animals usual nutrient'feed.

Compounds of the Formula I can be prepared by methods disclosed in U.S. application Ser. No. 154,674, filed June 18, 1971 now abandoned.

Unless otherwise specified, all percentages are given on a weight-to-weight basis. The pound (1b.) weights given are avoirdupois units.

Feeding of the compositions of the present invention can commence for birds shortly after hatching and in the case of mammals, during the creep-feeding period of suckling animals when they are starting on solid food and, of course, after weaning. Feeding ofthe compositions is continued throughout the growing period, lactation period, or egg-laying period.

The total concentration of the compound of the Formula 1 in the feed composition is determined with regard to the species of animal, age, weight, and average amount of feed consumed daily. Preferably the compound of the Formula 1 is employed in the finished feed that will supply the animal with a daily intake of from about 0.01 mg. to about 250 mg. per head per day.

The following table illustrates the range of compound of Formula 1 in milligrams daily dose per head per day for representative animals.

Range Preferred Animal Daily Dose/Head, mg. Daily Dose, mg.

Swine (birth to 8 weeks) 0.l25 12.5 0.7 Swine (40 to 200 lbs.) 0.725 72.5 4.0 Chickens (growing 0-8 weeks) 0.015 1.5 0.1 Hens (laying) 0.030 3.0 0.15 Turkeys (growing 0-24 weeks) 0.1 5.0 0.25 Beef Cattle (fattening) 2.5 250 14.0 Calves (0-12 weeks) 0.3 30 1.5 Dairy Cattle (lactation) 2.5 250 14.0 Lambs (fattening) 1.0

The foregoing dosage can generally be accomplished by providing from about mg. to about 12,500 mg. of

a compound of the Formula I per ton of finished feed.

Advantageously a compound of the Formula 1 is supplied in the form ofa liquid or solid premix wherein the concentration is 2,000 times greater than the de sired final concentration of the feed. For example, the compound of Formula 1 can be dissolved or suspended in a fluid vehicle such as corn oil, cottonseed oil, molasses, distillers solubles and the like to prepare a fluid premix. Alternatively, a solid premix can be prepared by mixing a compound of the Formula 1 with an edible solid diluent such as sucrose, lactose, starch, corn meal, flour, calcium carbonate, soybean meal and the like.

EXAMPLE I A diet for fattening lambs is prepared from the following types and amounts of ingredients:

Ground ear corn 82.05% Alfalfa meal 10.0 Soybean oil meal 44% 7.0 Ground limestone 0.3 Salt 0.6 7: Trace mineral mixture 0 05% Contains the following percent ofmincrals: Mn, 12; Co. 0.08; Fe, 5.0; Cu. 04; I, 0.24; Zn, 0.7.

I EXAMPLE 2 A chicken feed for broilers is prepared from the following types and amounts of ingredients:

Yellow corn meal 67.35% Soybean oil meal 24.00% Menhaden fish meal 6.00%

Consisting of 16.0 gm. Vitamin A supplement (l units/mg. 1'. 3.6 gm. Vitamin D supplement (15,000 units/gm.); 7.1 gm. riboflavin supplement (1 gm. riboflavin per ounce); 500 mg. niacin.

EXAMPLE 3 A fattening feed for 800 pound yearling cattle is prepared from the following types and amounts of ingredients:

Ground ear corn 89.75% Soybean oil meal, 44% 9.0 Ground limestone 0.7 Salt 0.5 Trace mineral mixture 0.05% Contains the following percent of minerals: Mn, 12:03, 0.08; Fe. 5.0; Cu, 0.4; l,

To 999 parts of the preceding feed is added 1 part of a premix composition prepared by mixing 1.5 gm. of 8-ch1oro-6-(o-chlorophenyl-l-cyclopropyl-4H-striazo1o-[4,3-a] [l,4]benzodiazepine with sufficient wheat flour to make 1 pound.

The feeding composition so prepared supplies 1.5 mg. of 8-chloro-6-(o-ch1orophenyl)-l-cyclopropy1-4H- s-triazolo[4,3-a] [l,4]benzodiazepine per pound, or about 3.3 parts per million.

Cattle are to receive the foregoing feed ad libitum together with 5 lb. of hay per head per day and when so fed have an increased rate of weight gain and improved utilization of feed.

EXAMPLE 4 A swine diet for growing hogs of 40 to 100 pounds body weight is prepared from the following types and amounts of ingredients:

Corn, ground 78.15% Soybean oil meal, 44% 17.0 Meat and bone scraps, 50% 3.0 7c Oyster shell flour 0.4 Bone meal 0.5 Salt 0.5 7: Trace mineral mixture 0.05% Zinc oxide 0.01% Vitamin A and D supplement 0.25% B Vitamin supplement 0.05% Vitamin B supplement 0.09%

Contains the following '7( of minerals: Mn, 12; Co. 0.08; Fe, 5.0; Cu, 0.4; l, 0.24; Zn, 0.7.

Contains 300 USP units D IGm. and 1500 l.U.A./Gm.

Contains per 1b.: Riboflavln, 2000 mg; calcium pantothcnatc. 4000 mg; niacin. 9000 mg; and choline chloride 10,000 mg.

Contains 6 mg. Vitamin 8. per lb.

To 999 parts of the preceding feed is added 1 part of a premix composition prepared by mixing 0.75 gm. of 8-chloro-6-(o-chlorophenyl)-l-cyclopropyl-4H-striazolo-[4,3-a] [l,4]benzodiazepine with sufficient ground limestone to make one pound.

The feeding composition so prepared supplies 0.75 mg. of 8-chloro-6-(o-chlorophenyl)-1-cyclopropyl-4H- s-triazolo[4,3-a] [l,4]benzodiazepine per pound, or about 1.65 parts per million.

The foregoing composition is usefully fed to hogs for increased rate of weight gain and improved utilization of feed.

EXAMPLE 5 Following the procedure of the preceding examples 1 to 4, inclusive, animal feeds are similarly prepared substituting equimolar amounts of:

8-chloro-1-cyclopropyl-6-phenyl-4H-s-triazolo[4,3- a]- [l ,4] benzodiazepine;

1-cyclopropyl-8-nitro-6-cyclopentyl-4H-s-triazolo- [43-21] [1 ,4]benzodiazepine;

1-cyclobutyl-8-chloro-6-(o-chlorophenyl)-4H-striazolo[4,3-a [l,4]benzodiazepine;

1-cyelopentyl-8-chloro-6-(2,6-difluorophenyl)-4H-striazolo[4,3-a] [l,4]benzodiazepine;

1-cyc1ohexyl-6-(2-pyridyl)-4H-s-triazolo[4,3-a] [1,4]-benzodiazepine;

l-cyclohexy1-8-methylsulfinyl-6-cyclohexyl-4H-striazolo[4,3-a] [l,4]benzodiazepine;

1-cyc1ooctyI-8,9-dicyano-6-(3-pyridyl)-4H-striazolo[4,3-a] 1,4]benzodiazepine;

1-cyc1opropyl-4,7,9-trimethyl-6-(cycloheptyl)-4H-striazolo[4,3-a] [l,4]benzodiazepine;

1-cyclopropyl-7,9-diethyl-6-(m-ethylphenyl)-4H-striazolo[4,3-a] 1,4]benzodiazepine;

l-cyclopropyl-8-chloro-6-(Z-pyrimidyl)-4H-striazolo[4,3-a] [l,4]benzodiazepine;

1-(cyclobutyl)-6-(2-pyrimidyl)-4Hs-triazolo[4,3- a][1,4]benzodiazepine;

1-cyclobutyl-6-phenyl-4H-s-triazolo[4,3-a] 1,4]benzodiazepine;

1-cyc1opentyl-7-chloro-6-(2-pyrimidyl)-4H-striazolo[4,3-a] [l,4]benzodiazepine;

1-cyclohexyl-8-trifluoromethyl-6-phenyl-4H-striazolo[4,3-a] [l,4]benzodiazepine;

1-cycloheptyl-8-bromo-6-phenyl-4H-s-triazolo[4,3- a]1,4]benzodiazepine;

1-cyclooctyl-9-chloro-6-phenyl-4H-s-triazolo[4,3-a1- 1,4]benzodiazepine;

1-cyclopropy1-8-cyano-6-cyclopentyl-4H-striazolo[4,3-a] [l,4]benzodiazepine;

1-cyclobutyl-8-chloro-6-cyclohexyl-4H-striazolo[4,3-a] [l,4]benzodiazepine;

l-cyelopentyl-8-chloro-6-cycloheptyl-4H-striazolo[4,3-a] 1,4]benzodiazepine;

l-cycloheptyl-8-chloro-6-(Z-pyridyl)-4H-striazolo[4,3-a] 1,4]benzodiazepine;

1-cyclooctyl-8-chloro-6-(2-furyl)- 4H-s-triazolo[4,3- a] [l,4]benzodiazepine;

1-cyclobuty1-8-chlor0-6-(3-pyridyl)-4H-striazolo[4,3-a] [l,4]benzodiazepine;

1-cyclopropyl-4-methyl-6-(2-pyridyl)-4H-striazolo[4,3-a] [l,4]benzodiazepine;

1-cyclopentyl-8-nitro-6-(o-chlorophenyl)-4H-striazolo[4,3-a] [l,4]benzodiazepine; 1-cyclohexyl-10- propylsulfonyl-8-methyl-6-phenyl-4H-s-triazolo[4,3-a] 1,4]benzodiazepine;

5 l-cyclopropyl-8-trifluoromethyl-6-( 3-pyridyl)-4H-striazolo[4,3-a] [1,41benzodiazepine;

lcyclobutyl-8-fluoro-6-(o-chlorophenyl)-4H-striazolo[4,3-a] [l,4]benzodiazepine;

l-cyclopropyl-8-iodo-4-methyl-6-(o-chlorophenyl)- 4H-s-triazolo[4,3-a] [l,4]benzodiazepine;

l-cyclopentyl-8,9-dicyano-6-(pmethylsulfinylphenyl)-4H-s-triazolo[4,3-a] zodiazepine;

l-cyclohexyl-lO-acetylamino-6-(4-pyrryll-4H-striazolo[4,3-a] [1,4lbenzodiazepine;

l-cycloheptyl-7,9-diethyl-6-cyclopentyl-4H-striazolo[4,3-a] [l,4]benzodiazepine;

1-cyclooctyl-8-methylsulfinyl-nitro-o-cyciohexyl-4H- s-triazolo[4,3-a] [l,4]benzodiazepine;

l-cyclopropyl-8, l -bis(dipropylamino )cycloheptyl- 4H-s-triazolo[4,3-a] [l,4]benzodiazepine;

8-chloro-l-cyclopropyl-6-phenyl-4H-s-triazolo[4,3- a]-[ l ,4]benzodiazepine--oxide;

8-chloro-l-cyclopropyl-6-(o-chlorophenyl)-4H-striazolo-[4,3-a] [1,4]benzodiazepine-5-oxide;

8-chloro-4-hydroxy-l-cyclopropyl-6-phenyl-4H-striazolo[4,3-a] [l,4]benzodiazepine acetate;

8-chloro-4-hydroxy-l-cyclopropyl-6-phenyl-4H-striazolo[4,3a] [l,4]benzodiazepine for the 8-chloro-6- (o-chlorophenyl)-l-cyclopropyl-4H-s-triazolo [4,3-a] [l,4]ben zodiazepine of the examples.

I claim:

1. A process for obtaining increased meat, milk or egg production comprising the feeding of from about 0.01 to about 250 mg./day of a compound selected from the group consisting of 1,6-disubstituted-4H-striazolo[4,3-a] [1,4]benzodiazepine of the formula:

in which R and R are selected from the group consist ing of hydrogen, alkyl of l to 3 carbon atoms, inclusive, halogen, nitro, cyano, trifluoromethyl and alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, amino, dialkylamino, and alkanoylamino, in which the carbon moieties are of l to 3 carbon atoms, inclusive; pyridyl (2, 3, or 4) and pyrimidyl; wherein R and R are defined like R and R the 5 N-oxides thereof and a pharmacologically acceptable salt thereof in combination with the nutrient feed to a healthy meat-producing, milkproducing or egg-laying animal.

2. The process of claim 1 wherein the member selected is in a concentration of from mg. to 12,500 mg. per pound of nutrient carrier in the form of a premix.

3. The process of claim 1 when the member selected is in the concentration from 250 mg. to 25,000 mg. per ton of feed.

4. The process of claim 1 wherein the compound is 8-chloro6-(o-chlorophenyl)-1-cyclopropyl-4H-striazolo[4,3-a] [l,4]-benzodiazepine.

5. The process of claim 2 wherein the compound is 8-chloro6-(o-chlorophenyl)-l-cyclopropyl-4H-striazolo[4,3-a] [1,4]-benzodiazepine.

6. The process of claim 3 wherein the compound is 8-chloro6-(o-chlorophenyl)-1-cyclopropyl-4H-striazolo[4,3-a] [l,4]-benzodiazepine. 

1. A process for obtaining increased meat, milk or egg production comprising the feeding of from about 0.01 to about 250 mg./day of a compound selected from the group consisting of 1,6-disubstituted-4H-s-triazolo(4,3-a) (1,4)benzodiazepine of the formula:
 1. A PROCESS FOR OBTAINING INCREASED MEAT, MILK OR EGG PRODUCTION COMPRISING THE FEEDING OF FROM ABOUT 0.01 TO ABOUT 250MG/DAY OF A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 1,6-DISUBSTITUTED-4H-S-TRIAZOLO(4,3-A) (1,4) BENZODIAZEPINE OF THE FORMULA:
 2. The process of claim 1 wherein the member selected is in a concentration of from 75 mg. to 12,500 mg. per pound of nutrient carrier in the form of a premix.
 3. The process of claim 1 when the member selected is in the concentration from 250 mg. to 25,000 mg. per ton of feed.
 4. The process of claim 1 wherein the compound is 8-chloro-6-(o-chlorophenyl)-1-cyclopropyl-4H-s-triazolo(4,3-a) (1,4)-benzodiazepine.
 5. The process of claim 2 wherein the compound is 8-chloro-6-(o-chlorophenyl)-1-cyclopropyl-4H-s-triazolo(4,3-a) (1,4)-benzodiazepine. 